The mood and anxiety disorders in their various permutations constitute a major source of personal suffering and impaired ability to engage in productive work and interpersonal relationships. Between 5 and 9% of women and between 2 and 3% of men meet the diagnostic criteria for major depression at any time; 10-25% of all women suffer major depression sometime in their lives, while 5-10% of men will develop major depressive disorder (American Psychiatric Association, 1994). The anxiety disorders obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, and generalized anxiety disorder (GAD) show lifetime prevalence rates of approximately 2.5%, 7%, 2.5%, and 5% respectively. Between 3 and 13% of individuals in community samples are regarded to meet the diagnostic criteria for social phobia. Mood and anxiety disorders are common comorbidities (American Psychiatric Association, 1994) and the most common antidepressant medicationsxe2x80x94including the serotonin reuptake inhibitors, the mixed serotonin-catecholamine reuptake inhibitors, the tricyclic antidepressants, and the monoamine oxidase inhibitorsxe2x80x94are all effective treatments for anxiety and panic attacks.
Affective disorders, while characterized by depressed mood of varying degrees, exist in various forms. Thus, melancholic depression is characterized by continuously-depressed mood and pervasive hopelessness, insomnia with early-morning awakening (with the inability to return to sleep), loss of appetite and weight loss, and excessive feelings of guilt (American Psychiatric Association, 1994). In contrast, so-called xe2x80x9catypicalxe2x80x9d depression is characterized by hypersomnia (oversleeping), hyperphagia and weight gain, andxe2x80x94oftenxe2x80x94mood reactivity. In generalxe2x80x94regardless of whether or not the depressive syndrome is melancholic, atypical, or some admixture of the twoxe2x80x94a diagnosis of major depression is given when depressed mood is present, or loss of interest or pleasure in all activities is present, for at least two weeks (American Psychiatric Association 1994). If less severe or incapacitating, depressed mood is considered dysthymia. Depressed mood can occur in the form of a cycling mood abnormality such as bipolar mood disorder, cyclothymia, or menstrual-related mood disorder.
Mood disorders are commonly seen in general medical practice and some general medical disorders resemble depression in important respects. In particular, both fibromyalgia and chronic fatigue syndrome are medical disorders that have clinical and pathophysiologic features in common with atypical depression.
It is widely accepted that the hypothalamic-pituitary-adrenocortical axis is dysregulated in patients with major depression. One of the early findings of biological psychiatry was that approximately 50% of depressed patients showed hypercortisolemiaxe2x80x94increased concentrations of the circulating steroid cortisol, produced by the adrenal cortex (Sachar 1967). This led to the hypothesis that the principle central nervous system (CNS) effector of the HPA axis, corticotropin-releasing hormone (CRH), was hypersecreted in depressed patients. Elevated levels of CRH in the cerebrospinal fluid (CSF) of depressed patients were subsequently observed, consistent with this hypothesis (Nemeroff et al 1984, Banki et al 1987, Arato et al 1989). Similarly, some patients with anxiety disordersxe2x80x94such as post-traumatic stress syndromexe2x80x94have elevated CSF levels of CRH (Baker et al 1999). However, it has also become appreciated that many depressed patients, with or without anxiety disorders, do not show hypercortisolemia and, in fact, show evidence of an insufficient or pathologically inactive hypothalamic-pituitary-adrenocortical axis (Casper et al., 1988, Vanderpool et al., 1991). These patients, most often the atypically depressed or eucortisolemic, have low CSF CRH levels (Geracioti et al., 1992 and 1997). Evidence of low CRH activity has also been found in patients with chronic fatigue syndrome and fibromyalgia (Demitrack and Crofford 1998).
Mood and anxiety disorders very frequently coexist in the same individual. In this regard, it is now appreciated that almost all antidepressants improve anxiety symptoms. Conversely, the most popular anxiolytics, the benzodiazepines, improve mood acutely but are typically ineffective or harmful to mood during chronic use.
The current psychopharmacologic treatments of affective and anxiety disorders are limited. A significant portion of depressed patients are resistant to treatment with existing antidepressants or combinations thereof either because of non-responsiveness or because a positive effect wears off (breakthrough depression) or is inadequate (depression in partial remission). Troubling side effects may also be seen with existing antidepressants. After beginning daily administration, psychopharmacologic anti-depressants at present have a latency of typically two weeks before the onset of significant antidepressant activity. As noted, antidepressant drugs are also used to treat anxiety disorders; the limitations of these drugs in treating anxiety are similar to those faced in attempts to treat depression: many patients are resistant to treatment or gain only partial or short-lasting responses; the common side effects are troubling (for example, the serotonin-reuptake inhibitors are the drugs most commonly used to treat unipolar depression and the most commonly-used agents to treat obsessive-compulsive disorder; these agents may have significant, unwanted sexual and/or gastrointestinal side effects in both male and female patientsxe2x80x94among other side effectsxe2x80x94and are either ineffective or only partially effective in a substantial percentage of patients). The most commonly used anxiolytic medications, the benzodiazepines, have a number of major limitations: (a) tolerance to their effects rapidly develops, with increasing doses becoming required to achieve the same effect; (b) benzodiazepine dependence is a standard occurrence after chronic use; (c) major withdrawal syndromes are seenxe2x80x94including grand mal seizuresxe2x80x94after abrupt discontinuation; (d) overdose is associated with respiratory depression and sometimes death; (e) effects are potentiated by alcohol, which is cross-tolerant with the benzodiazepines; and (f) high abuse potential.
In a series of in vitro and in vivo behavioral experiments we find that subhypnotic doses of oleamide have actions predictive of anti-anxiety and antidepressant effects. Our data also indicate that it has a rapid onset of action. Specifically, we found that oleamide acutely increases CRH messenger ribonucleic acid (mRNA) expression in explanted hypothalamic cell cultures in a concentration-dependent manner and also stimulates release of CRH from these cells. See FIGS. 1 and 2. This effect (increase in CRH mRNA in the hypothalamus) is also seen after electroconvulsive therapy (ECT) in rats (Brady et al 1994). ECT has potent antidepressant effects. In fact, the clinically-used antidepressant medications tested, such as the tricyclic antidepressants, the serotonin-reuptake inhibitors, and monoamine oxidase inhibitors, all modify brain CRH mRNA levels (Brady et al 1991 and 1992). Moreover, dysregulation of CNS CRH release is regarded to be of fundamental pathophysiologic significance in clinical depression (Gold et al 1988). Our behavioral findings support our in vitro observations about the antidepressant and anxiolytic effects of oleamide. Specifically, IP dosing of oleamide enhances exploratory behavior on the elevated plus maze in the context of decreasing overall activity.
The present invention relates to a method for treating mood and anxiety disorders in humans or animals in need of such treatment by administering a safe and effective dose of oleamide, an oleamide analog, an inhibitor of oleamide degradation or clearance, or an oleamide antagonist.